Cancer-related fatigue: Towards a more targeted approach based on classification by biomarkers and psychological factors.

Cancer-related fatigue is a frequent, burdensome and often insufficiently treated symptom. A more targeted treatment of fatigue is urgently needed. Therefore, we examined biomarkers and clinical factors to identify fatigue subtypes with potentially different pathophysiologies. The study population comprised disease-free breast cancer survivors of a German population-based case-control study who were re-assessed on average 6 (FU1, n = 1871) and 11 years (FU2, n = 1295) after diagnosis. At FU1 and FU2, we assessed fatigue with the 20-item multidimensional Fatigue Assessment Questionnaire and further factors by structured telephone-interviews. Serum samples collected at FU1 were analyzed for IL-1ß, IL-2, IL-4, IL-6, IL-10, TNF-a, GM-CSF, IL-5, VEGF-A, SAA, CRP, VCAM-1, ICAM-1, leptin, adiponectin and resistin. Exploratory cluster analyses among survivors with fatigue at FU1 and no history of depression yielded three clusters (CL1, CL2 and CL3). CL1 (n = 195) on average had high levels of TNF-α, IL1-ß, IL-6, resistin, VEGF-A and GM-CSF, and showed high BMI and pain levels. Fatigue in CL1 manifested rather in physical dimensions. Contrarily, CL2 (n = 78) was characterized by high leptin level and had highest cognitive fatigue. CL3 (n = 318) did not show any prominent characteristics. Fatigued survivors with a history of depression (n = 214) had significantly higher physical, emotional and cognitive fatigue and showed significantly less amelioration of fatigue from FU1 to FU2 than survivors without depression. In conclusion, from the broad phenotype "cancer-related fatigue" we were able to delineate subgroups characterized by biomarkers or history of depression. Future investigations may take these subtypes into account, ultimately enabling a better targeted therapy of fatigue.

Patterns and influencing factors of exercise attendance of breast cancer patients during neoadjuvant chemotherapy.

BACKGROUND: Performing 2-3 exercise sessions/week may relieve therapy-related side effects of breast cancer patients (BRCA) and improve their quality of life. However, attendance to the exercise sessions is often impaired. Thus, we investigated patterns and possible influencing factors of attendance to an aerobic (AT) or resistance training (RT) intervention in BRCA during neoadjuvant chemotherapy. METHODS: BRCA (N = 122) were randomly allocated to supervised AT or RT twice weekly during neoadjuvant chemotherapy (18 ± 4 weeks). Attendance was calculated individually and group-wise per training week as the percentage of the performed sessions out of the prescribed sessions. Possible influencing factors were investigated using multiple regression analyses. RESULTS: Mean individual attendance was 44.1% ± 29.3% with no significant differences between the groups. Group-wise attendance was highest in the first 6 weeks of training with ≥ 60% for AT and ≥ 50% for RT, but decreased over the course of the intervention accompanying chemotherapy. Significantly higher attendance was associated with not having vs. having nausea (ß = - 14.57; p = 0.007) and not having vs. having pain (ß = - 12.07; p = 0.12), whereas fatigue did not show any association (ß = - 0.006; p = 0.96). Having been randomized into a preferred intervention group (48.8%) showed no association with attendance. Yet, patients' rating of the exercise intervention as "good"/ "very good" (58.7%) was significantly associated with higher attendance (p = 0.01). CONCLUSION: For both exercise interventions, group-wise attendance/training week decreased during chemotherapy despite good intervention ratings. While some patients never started, others trained almost constantly twice weekly. The study revealed that patients who are nauseous or experience pain may need more support to attend more exercise sessions. Trial Registration Clinicaltrials.gov: NCT02999074 from May 6, 2016.

Dropout from exercise trials among cancer survivors-An individual patient data meta-analysis from the POLARIS study.

INTRODUCTION: The number of randomized controlled trials (RCTs) investigating the effects of exercise among cancer survivors has increased in recent years; however, participants dropping out of the trials are rarely described. The objective of the present study was to assess which combinations of participant and exercise program characteristics were associated with dropout from the exercise arms of RCTs among cancer survivors. METHODS: This study used data collected in the Predicting OptimaL cAncer RehabIlitation and Supportive care (POLARIS) study, an international database of RCTs investigating the effects of exercise among cancer survivors. Thirty-four exercise trials, with a total of 2467 patients without metastatic disease randomized to an exercise arm were included. Harmonized studies included a pre and a posttest, and participants were classified as dropouts when missing all assessments at the post-intervention test. Subgroups were identified with a conditional inference tree. RESULTS: Overall, 9.6% of the participants dropped out. Five subgroups were identified in the conditional inference tree based on four significant associations with dropout. Most dropout was observed for participants with BMI >28.4 kg/m2 , performing supervised resistance or unsupervised mixed exercise (19.8% dropout) or had low-medium education and performed aerobic or supervised mixed exercise (13.5%). The lowest dropout was found for participants with BMI >28.4 kg/m2 and high education performing aerobic or supervised mixed exercise (5.1%), and participants with BMI ≤28.4 kg/m2 exercising during (5.2%) or post (9.5%) treatment. CONCLUSIONS: There are several systematic differences between cancer survivors completing and dropping out from exercise trials, possibly affecting the external validity of exercise effects.

Longitudinal associations of bioelectrical phase angle and fatigue in breast cancer patients.

Cancer-related fatigue is commonly treated in an undifferentiated manner, because its pathophysiology is still not well understood. Therefore, we investigated if bioelectrical phase angle (PhA), a non-invasive marker of cell integrity, could help to single out specific fatigue subtypes. In a randomized controlled strength training intervention trial, PhA was measured by bioelectrical impedance analysis in 158 breast cancer patients. Fatigue was assessed with the multidimensional 20-item Fatigue Assessment Questionnaire. Multiple regression analyses considering changes in PhA and fatigue from baseline to post-intervention and ANCOVA models investigating the strength training effect on PhA were conducted. Further, explorative mediation and moderation analyses were performed. Decrease (=worsening) in PhA was significantly associated with increase in physical (P = .010) and emotional (P = .019) fatigue. These associations were markedly stronger in patients with normal BMI (interaction P = .059 and .097) and with low pre-diagnosis exercise level (interaction P = .058 and .19). Among patients with normal BMI strength training was associated with an increase in PhA (ANCOVA P = .059), but not among overweight/obese patients (interaction P = .035). Chemotherapy was a major determinant for low PhA, but PhA did not mediate the effect of chemotherapy on fatigue. In conclusion, PhA has a significant inverse association with physical and emotional fatigue. This association is moderated by BMI and previous exercise. Significant relationships of PhA were also observed with chemotherapy and strength training. Thus, PhA might be a marker that could help in the classification of subtypes of fatigue with different pathophysiology, which may require specifically tailored treatment. Further research on this is warranted.

Long-term effects of exercise interventions on physical activity in breast cancer patients: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Benefits of exercise interventions for cancer patients are well established. This systematic review aimed to investigate the sustainability of exercise interventions with respect to physical activity behaviour of breast cancer patients in the longer term. METHODS: The databases Pubmed, Cochrane, Embase, and Web of Science were systematically searched for randomized controlled trials (RCTs) investigating aerobic exercise, resistance exercise, or combined exercise interventions in breast cancer patients and assessing physical activity at least 2 months after the intervention. Random-effect models were used to calculate standardized mean differences (SMD). RESULTS: A total of 27 RCTs with 4120 participants were included in the review, of which 11 RCTs with 1545 participants had appropriate data for the meta-analyses. Physical activity was mainly self-reported, and most exercise interventions were supervised. Exercise interventions tended to show a moderate significant effect up to 6 months for moderate to vigorous physical activity (SMD [95% CI] = 0.39 [0.07, 0.70]) and small, non-significant effects on total physical activity at 6 months (SMD [95% CI] = 0.14 [- 0.00, 0.28]) and up to 60 months after the intervention (SMD = 0.29 [-0.31, 0.90]). Differences between intervention characteristics, such as supervised versus unsupervised, were inconclusive due to the small number of RCTs. CONCLUSIONS: The physical activity behaviour in breast cancer patients remained improved for several months beyond the end of exercise interventions, but effects were small to moderate and diminished over time. Future studies should clarify how to maintain a healthy level of physical activity after completion of an exercise intervention.

Psycho-oncologists' knowledge of cancer-related fatigue and the targets for improving education and training: results from a cross-sectional survey study.

PURPOSE: To explore psycho-oncologists' knowledge of cancer-related fatigue and their self-efficacy to intervene for fatigue. We further aimed to examine the role of fatigue in psycho-oncological training and derive specific suggestions for improvements. METHODS: For this cross-sectional survey study, psycho-oncologists working in Germany were systematically recruited via an address directory or invited by training institutes or colleagues. The online survey encompassed questions on knowledge of fatigue guidelines and interventions, self-efficacy, counseling, and fatigue in professional training. Data were analyzed descriptively and using Mann-Whitney U tests. A logistic regression analysis was performed to identify variables linked to fatigue guideline knowledge. RESULTS: Seventy two percent of the 144 surveyed psycho-oncologists stated not knowing any fatigue-specific guidelines. Those unaware of guidelines reported a lower self-efficacy to intervene for fatigue. However, despite low knowledge of the guidelines, more than 80% of the participants felt well informed about fatigue and reported high self-efficacy. Most participants were aware of the empirical evidence for psychotherapeutic interventions (95%); everyday physical activity, e.g., taking a walk (98%); yoga (82%); and mindfulness-based interventions (82%). Knowledge gaps existed concerning the evidence of resistance/endurance training for treating fatigue. Knowing that resistance/endurance training is an effective treatment was related to an increased frequency to recommend it to patients. Suggestions to improve training for psycho-oncologists included raising awareness earlier in the career path and offering multidisciplinary trainings for fatigue. CONCLUSION: To improve fatigue-related guideline knowledge among psycho-oncologists and enhance implementation into clinical practice multidisciplinary trainings are needed. Psycho-oncologists should play an important role in fatigue management. TRIAL REGISTRATION: Clinicaltrials.gov , identifier: NCT04921644. Registered in June 2021.

Late effects, long-term problems and unmet needs of cancer survivors.

Great efforts are being made in cancer treatment, with impressive improvement in survival. The situation concerning research and care for long-term problems and late effects in the growing population of cancer survivors, however, is unsatisfactory. Therefore, in the FiX survey 1348 disease-free survivors about 4 years after diagnosis of different cancer types were asked to rate existing burdens and support received for them along a list of 36 potential problems. Health-related quality of life (HRQoL) was assessed with the EORTC QLQ-C30. Determinants of burdens were explored using logistic regression analysis. While cancer survivors' global HRQoL, physical and role function ratings were comparable or better than age- and sex-matched reference values of the general population, emotional and cognitive function was worse, especially among women (P < .01). Most frequently reported problems with at least moderate burden were loss of physical performance (36.3%), fatigue (35.1%), sexual problems (34.7%), sleep problems (34.1%), arthralgia (33.8%), anxiety (28.0%), neuropathy (25.6%), memory problems (23.0%) and concentration problems (21.9%). Burdened survivors often rated received support as poor, especially regarding support for problems that physicians might consider medically nonthreatening, or for which no effective pharmacologic or medical treatment is known. Determinants for burden included higher age, female gender, having ever received chemotherapy and overweight/obesity. In conclusion, a significant number of cancer survivors suffer from long-term or late effects and have unmet care needs. Awareness of health care professionals should be increased for these issues. The results of our study can contribute to the development of targeted survivorship plans.

Cancer-related fatigue: Identification of hallmarks to enable refined treatment approaches.

OBJECTIVE: Recommendations for fatigue management are commonly given in an undifferentiated manner without further evaluation of patient's specific symptomatology. Thus, we aimed to identify hallmarks of potential fatigue subgroups which might guide more refined treatment. METHODS: The FiX study assessed fatigue with the EORTC QLQ-FA12 in patients around 2 years after cancer diagnosis (T0) including 15 different entities. After 2 years, a follow-up survey (T1) was conducted. The analyses comprised all patients with prevalent fatigue at T0 (N = 1023). Hierarchical cluster analysis was performed using the Ward method and including the dichotomized factors emotional distress, pain, insomnia, and obesity. Emotional distress, that is, depressive symptoms and anxiety, was assessed by the PHQ-4. Pain and insomnia were based on the according symptom scores of the EORTC QLQ-C30. Analysis of covariance was conducted to investigate the association of the fatigue clusters at T0 with subsequent fatigue at T1. RESULTS: Four hierarchical clusters were identified. The first cluster comprised patients with moderate-to-severe distress. The remaining fatigue cases were differentiated by obesity and then by pain. Fatigue cases without any of these three symptoms formed the last cluster. Physical, emotional and cognitive fatigue were highest in the distress cluster. Additionally, this cluster was associated with higher physical, emotional and cognitive fatigue at T1 compared to the other clusters. CONCLUSIONS: Fatigue in conjunction with emotional distress had worse impact, persisted longer, and may require other treatment approaches than fatigue in patients without emotional distress. Obesity and pain may be further distinguishing hallmarks for refined fatigue management.

The cancer patients' perspective on feasibility of using a fatigue diary and the benefits on self-management: results from a longitudinal study.

PURPOSE: To evaluate the patients' perspective on feasibility of using a fatigue diary and its benefits on self-management. METHODS: This longitudinal study enrolled 50 cancer patients in routine care. Following baseline (t0) assessment, patients were asked to complete a 7-day fatigue diary and subsequently obtained written diary evaluation. Feasibility, benefits, and fatigue-related attitudes were assessed via self-report 1 (t1) and 4 months (t2) after distributing the diary. Data were analyzed descriptively and using Wilcoxon signed-rank tests. RESULTS: Most patients (94%) completed the diary for 7 days and rated feasibility as high. After diary completion and receiving the evaluation, fewer patients felt helpless in the face of fatigue (t1: 21% vs. t0: 53%). Additionally, more patients addressed fatigue with their general practitioner (t2: 49% vs. t0: 36%) and pro-actively searched for information and help (t2: 59% vs. t0: 38%). The diary enabled a majority of patients to be aware of their fatigue patterns, to plan daily routines accordingly and to take adequate actions against fatigue. CONCLUSION: The study showed that symptom monitoring via a fatigue diary was considered feasible and enhanced self-management in cancer patients. Thus, fatigue diaries might be a useful measure contributing to an improved fatigue management. The results reinforce guideline recommendations for routine application of fatigue diaries in clinical care. Healthcare professionals should encourage patients to fatigue diary use and provide individually tailored counseling based on diary entries.

Cancer-related fatigue: benefits of information booklets to improve patients' knowledge and empowerment.

PURPOSE: To investigate cancer patients' knowledge and attitudes regarding fatigue and the potential benefits and acceptability of a brief information booklet. METHODS: The CARPE DIEM study assessed knowledge and attitudes regarding fatigue in a diverse group of 50 cancer patients before (T0) and about one (T1) and four months (T2) after reading the booklet. At T1, participants additionally rated its usefulness. RESULTS: At baseline, 37.5% of respondents did not know the term "fatigue" or what it meant. Those who already knew something about fatigue mainly had obtained their information from booklets, books, or articles (63.3%) and/or the internet (46.7%). Overall, knowledge gaps existed, particularly about potential fatigue treatment options and whether fatigue is an indicator of cancer progression. Furthermore, 56.4% felt poorly informed, and 46.1% reported feeling helpless in the face of fatigue. Lower knowledge at baseline was significantly associated with lower education and older age. At T1 and T2, there were significant improvements in several knowledge questions and attitudes. Patient-reported benefits included getting new information about fatigue (91.1%), awareness of not being alone with their problems (89.7%), taking appropriate actions (72.9%), and encouragement to talk about their fatigue with family/friends (55.3%) or with a health professional (52.7%). CONCLUSIONS: Specific gaps were identified in the provision of information and education for cancer patients about fatigue. A low-cost intervention asking to read a brief information booklet was associated with improved knowledge. This could be considered as a first step offered as part of a bundle of further efforts to improve knowledge and care of fatigue.

Comparison of subjectively and objectively assessed sleep problems in breast cancer patients starting neoadjuvant chemotherapy.

PURPOSE: To characterize sleep problems and to compare subjective and objective assessments in breast cancer patients starting neoadjuvant chemotherapy. METHODS: Sleep characteristics of 54 breast cancer patients starting neoadjuvant chemotherapy were analyzed. Subjective sleep characteristics were assessed with the Pittsburgh Sleep Quality Index (PSQI) and objective sleep measurements with an accelerometer (ActiGraph wGT3X-BT) worn on the wrist for 7 consecutive days. RESULTS: According to the common PSQI cut-off of 8, 10 (18.87%) of the patients were poor sleepers. ActiGraph measures did not mirror this classification as values for poor, and good sleepers did not differ significantly. Overall, Bland-Altman plots illustrated higher ActiGraph values for sleep efficiency and effective sleep time and lower values for sleep latency, compared with PSQI. For total sleep time, less disagreement between both measures was observed. Actigraphy was limited in precise identification of sleep begin and sleep latency but provided supplementary information about number and minutes of awakenings during the night. CONCLUSION: Subjective and objective measurement methods differed substantially in various parameters, with limitations in both methods. A combination of both methods might be most promising. TRIAL REGISTRATION: Clinicaltrials.gov : NCT02999074.

Knowledge, perceptions, and management of cancer-related fatigue: the patients' perspective.

PURPOSE: This study aimed to assess cancer patients' knowledge and perceptions regarding fatigue and to provide up-to-date information on the current fatigue management from the patients' perspective. METHODS: The FiX study recruited 2508 cancer patients approximately 2 years after diagnosis via a cancer registry in Germany. Participants completed a questionnaire on their knowledge and perceptions of fatigue and the management received. RESULTS: More than half of respondents (58%), especially among the elderly patients, did not feel well informed about fatigue. Overall, 41% reported having never been asked about being exhausted by their treating physician. Even fewer patients stated that general practitioners or nurses have asked if they felt exhausted. Only 13% of patients who had experienced severe fatigue had received a fatigue assessment by means of a rating scale or questionnaire-although this is recommended by existing guidelines for fatigue screening. Health care professionals seemed less likely to address fatigue with elderly as well as female patients. The most commonly reported measure against fatigue was exercise or regular physical activity (68%). However, this was mostly done on patients' own initiative. Psychological support was rarely used (13%) and only in approximately half of the cases upon the advice of a physician. Yoga, another promising intervention against fatigue, was performed by only 9% of patients. CONCLUSIONS: Our study indicates deficits in terms of knowledge, education, screening, counseling, and treatment for fatigue and highlights starting points for targeted improvements in fatigue management based on patients' needs.

Resistance Exercise Modulates Kynurenine Pathway in Pancreatic Cancer Patients.

The aim of this study was to investigate the impact of Supervised and Home-based resistance exercise on the Kynurenine pathway in patients with pancreatic cancer who underwent surgery and chemotherapy. In the SUPPORT study, adult pancreatic cancer patients were randomized to intervention programs of 6-month (1) a Supervised moderate-to-high-intensity progressive resistance training or (2) unsupervised Home-based resistance training, or (3) to a standard care patient Control group. Serum levels of kynurenine, tryptophan and IL-6 were assessed for 32 participants before, after 3 months and after 6 months of exercise intervention. Group differences were investigated using analysis-of-covariance. Patients in the Supervised training group showed decreased levels of serum kynurenine and kynurenine/tryptophan ratio (p = 0.07; p = 0.01 respectively) as well as increased Tryptophan levels (p = 0.05) in comparison to Home-based and Control group over time. The Home-based exercise group had significant increased kynurenine and kynurenine/tryptophan ratio levels. IL-6 levels decreased over the first three months for both intervention groups as well as the Control group (Supervised: p < 0.01, Home-based: p < 0.010, Control group: p < 0.01). Supervised resistance exercise might positively regulate the Kynurenine pathway and downregulate the kynurenine/tryptophan (indicative of IDO/TDO enzyme) levels, hence modulating the immune system.

Effects of physical and mind-body exercise on sleep problems during and after breast cancer treatment: a systematic review and meta-analysis.

PURPOSE: We conducted a meta-analysis evaluating the effects of different exercise interventions on self-reported and objective sleep measurements during or after breast cancer treatment. METHODS: Three databases were systematically searched for randomized controlled trials with any type of exercise intervention in women with breast cancer. Outcomes were self-reported or objective sleep measurements. Standardized mean differences (SMDs) were calculated using random-effects models. RESULTS: The meta-analysis included 22 trials with 2107 participants. Of these, 17 studies used the Pittsburgh Sleep Quality Index (PSQI), six studies included objective sleep assessments (ActiGraph). Physical exercise interventions included walking, aerobic exercise, resistance exercise or a combination of both. Mind-body exercise interventions included yoga, Tai Chi and Qigong. Most interventions were supervised. Both, physical (SMD - 0.32; 95% CI - 0.54 to - 0.10) and mind-body exercise interventions (SMD - 0.27; 95% CI - 0.44 to - 0.09), resulted in improvements of total sleep scores. Subgroup analyses revealed no clear differences between interventions conducted during versus after breast cancer treatment. Considering the PSQI subscales, exercise resulted in improvements of sleep quality (SMD - 0.28; 95% CI - 0.44 to - 0.11) and sleep disturbances (SMD - 0.26; 95% CI - 0.45 to - 0.06). Regarding the objective measurements, no significant effects were found. CONCLUSIONS: Physical as well as mind-body exercise can improve subjective sleep problems in breast cancer patients. In contrast, there was no effect of exercise on objective sleep measures. Future studies should clarify which type of intervention might be most effective depending on individual patients' and treatments' characteristics.

Return to work after breast cancer: The role of treatment-related side effects and potential impact on quality of life.

For breast cancer survivors return to work (RTW) is important from an economic, societal and personal perspective. Thus, we investigated the impact of side effects and other factors on RTW. Five years post-diagnosis 135 disease-free breast cancer survivors below retirement age who were employed pre-diagnosis recorded their current and previous working status and reasons for impaired RTW. Patient-reported outcomes were prospectively reported over the cancer continuum. One year post-surgery 57% of survivors worked the same and 22% with reduced working time compared to pre-diagnosis. Logistic regression revealed significant associations of depressive symptoms, arm morbidity, lower education and younger age with impaired RTW after 1 year, and persisting physical fatigue and living with partner with impaired RTW after 5 years. Major self-reported reasons included fatigue and cognitive problems. Temporal patterns of general quality of life (QoL), physical, cognitive and role function, and financial problems were significantly worse among women with no RTW compared to those working again. In conclusion, cessation of work after breast cancer seems associated with worse QoL. Fatigue, psychological and cognitive problems as well as arm morbidity seemed to hinder RTW. Thus, a better management of these problems might help women to stay in working life.

Effects and moderators of exercise on muscle strength, muscle function and aerobic fitness in patients with cancer: a meta-analysis of individual patient data.

OBJECTIVE: To optimally target exercise interventions for patients with cancer, it is important to identify which patients benefit from which interventions. DESIGN: We conducted an individual patient data meta-analysis to investigate demographic, clinical, intervention-related and exercise-related moderators of exercise intervention effects on physical fitness in patients with cancer. DATA SOURCES: We identified relevant studies via systematic searches in electronic databases (PubMed, Embase, PsycINFO and CINAHL). ELIGIBILITY CRITERIA: We analysed data from 28 randomised controlled trials investigating the effects of exercise on upper body muscle strength (UBMS) and lower body muscle strength (LBMS), lower body muscle function (LBMF) and aerobic fitness in adult patients with cancer. RESULTS: Exercise significantly improved UBMS (ß=0.20, 95% Confidence Interval (CI) 0.14 to 0.26), LBMS (ß=0.29, 95% CI 0.23 to 0.35), LBMF (ß=0.16, 95% CI 0.08 to 0.24) and aerobic fitness (ß=0.28, 95% CI 0.23 to 0.34), with larger effects for supervised interventions. Exercise effects on UBMS were larger during treatment, when supervised interventions included ≥3 sessions per week, when resistance exercises were included and when session duration was >60 min. Exercise effects on LBMS were larger for patients who were living alone, for supervised interventions including resistance exercise and when session duration was >60 min. Exercise effects on aerobic fitness were larger for younger patients and when supervised interventions included aerobic exercise. CONCLUSION: Exercise interventions during and following cancer treatment had small effects on UBMS, LBMS, LBMF and aerobic fitness. Demographic, intervention-related and exercise-related characteristics including age, marital status, intervention timing, delivery mode and frequency and type and time of exercise sessions moderated the exercise effect on UBMS, LBMS and aerobic fitness.

Determinants of physical, affective, and cognitive fatigue during breast cancer therapy and 12 months follow-up.

Fatigue is common in cancer survivors but often insufficiently treated. Due to its complexity a one-size-fits-all treatment seems not appropriate. To gain more information on influencing factors and sub-dimensions of fatigue we investigated potential determinants and correlates of physical, affective, and cognitive fatigue in breast cancer survivors during and after adjuvant therapy. Within the follow-up of two randomized controlled trials physical, affective, and cognitive fatigue were repeatedly assessed during and up to 12 months after cancer therapy with the 20-item Fatigue Assessment Questionnaire in 255 breast cancer survivors. Determinants of the different fatigue dimensions over time were explored with linear mixed models. Chemotherapy appeared as significant precipitating factor for physical fatigue. However, type of cancer therapy had no impact on fatigue one year post-treatment. Obesity was significantly associated with increased physical fatigue throughout all time points (Δ=15.5 at 12 months) whereas exercise appeared to be beneficial (Δ = -6.3). In contrast, affective fatigue was significantly associated with poor social support and worries about the future. In addition, poor sleep quality and previous use of psychopharmaceuticals were significantly associated with physical, affective, as well as cognitive fatigue. Further, hot flashes were associated with increased physical and cognitive fatigue. In conclusion, the broad diagnosis 'fatigue' in cancer survivors needs to be recognized as a diversity of symptoms determined by specific characteristics and likely different etiologies. Taking potential influencing factors such as obesity, physical inactivity, sleep problems, hot flashes, lack of social support, or psychological disorders into consideration might enable a better, individually-tailored fatigue treatment.

Effects of physical exercise on markers of inflammation in breast cancer patients during adjuvant chemotherapy.

PURPOSE: Exercise has been shown to reduce fatigue during cancer treatment. Hypothesized mechanisms include inflammatory pathways. Therefore, we investigated effects of exercise on markers of inflammation in breast cancer patients during adjuvant chemotherapy. METHODS: We pooled data from two randomized controlled exercise intervention trials with breast cancer patients during adjuvant chemotherapy (n = 130), which had previously shown beneficial effects of exercise on fatigue. Exercise comprised a 12-week resistance training (BEATE study) or an 18-week combined resistance and aerobic training (PACT study). Serum IL-6, IL-1ra, and the IL-6/IL-1ra ratio were quantified at baseline, mid-intervention, post-intervention, and 6-9 months post-baseline. RESULTS: Mixed effect models showed significant increases in IL-6 and IL-6/IL-1ra ratio during chemotherapy and decreases afterwards. Differences between exercise and control group were not significant at any time point. Changes in total cancer-related fatigue were significantly correlated with changes in IL-6/IL-1ra ratio (partial correlation r = 0.23) and IL-6 (r = 0.21), and changes in physical cancer-related fatigue with changes in IL-6/IL-1ra ratio (r = 0.21). CONCLUSIONS: Changes in fatigue were slightly correlated with changes in inflammatory markers, and there was a strong inflammatory response to adjuvant chemotherapy. The supervised exercise training did not counteract this increase in inflammation, suggesting that beneficial effects of exercise on fatigue during adjuvant chemotherapy for breast cancer are not essentially mediated by IL-6, IL-1ra, or the IL-6/IL-1ra ratio.

L-Thyroxine intake as a potential risk factor for the development of fatigue in breast cancer patients undergoing chemotherapy.

PURPOSE: L-Thyroxine is one of the most commonly prescribed drugs and accordingly used by many breast cancer patients with thyroid disorders. Hence, potential interactions of chemotherapy with L-thyroxine, possibly contributing to fatigue, would be of high clinical relevance. Therefore, we investigated fatigue and underlying pathways in L-thyroxine-using breast cancer patients during chemotherapy. METHODS: Thyroid-stimulating hormone (TSH), L-triiodothyronine (T3), and diurnal salivary cortisol patterns were analyzed in breast cancer patients in the beginning and at the end of adjuvant chemotherapy within the control group (n = 41) of a randomized exercise intervention trial. Additionally, relationships in the exercising group (n = 45) as well as in healthy women (n = 25) were explored. Regression and mediation analyses were performed. RESULTS: L-Thyroxine use was significantly associated with lower TSH (median = 0.33 mU/l, interquartile range = (0.15-0.48)), whereas patients not using L-thyroxine had TSH comparable to healthy women (0.51 mU/l (0.37-0.74)). T3 significantly declined during chemotherapy in L-thyroxine users but not in non-users. However, the group difference failed statistical significance. L-Thyroxine treatment was significantly associated with increased physical fatigue during chemotherapy (p = 0.004) in the non-exercising group. This association appeared to be partly mediated by TSH. Further, TSH appeared to affect fatigue partly via increased cortisol levels. In the exercise group, there was no significant association between L-thyroxine and fatigue. CONCLUSIONS: L-Thyroxine treatment during chemotherapy might result in hormonal dysregulations that can contribute to increased physical fatigue. Therefore, breast cancer patients on L-thyroxine treatment may need special monitoring of their thyroid levels and of fatigue during chemotherapy and should be encouraged to exercise. TRIAL REGISTRATION: ClinicalTrials.gov NCT01106820.

Exercise behavior and physical fitness in patients with advanced lung cancer.

PURPOSE: The aim of this work was to evaluate exercise behavior and physical fitness of advanced lung cancer patients shortly after primary diagnosis. METHODS: Between November 2013 and December 2016, advanced lung cancer patients (n = 227, mean age 62.2 years) were enrolled shortly after diagnosis and 211 patients were tested for endurance capacity (six-minute walk test) and strength performance (maximum voluntary isometric contraction of upper and lower extremities). Current and previous exercise and walking behavior were assessed using a self-reported questionnaire regarding type, frequency, intensity, and duration. Paired Student's t tests were used to compare physical fitness to reference data. The relation of potential determinants with physical fitness was assessed using linear regression analysis. RESULTS: Exercise behavior was superior in the year before diagnosis compared to the time of study enrollment. Patients reduced frequency, intensity, and duration of sports/exercise after their lung cancer diagnosis. We observed significantly lower endurance capacity (p < .01) and strength performance in lower extremities (p < .01) in male and female patients compared to age and sex-matched reference data. We found significant correlations of previous exercise and walking behavior with physical fitness shortly after diagnosis in patients with advanced lung cancer. CONCLUSION: Patients with advanced lung cancer showed impaired physical fitness regarding endurance and strength capacity. The strong decline in participation of sports/exercise shortly after diagnosis supports early implementation of physical exercise during anti-cancer treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT02055508.